Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion (36 mumol per kg bw per min), and during 30 mins of cycling exercise at 75% of maximal oxygen uptake while the lactate infusion continued to establish arterial lactate concentrations of 0.89+/-0.08, 3.9+/-0.3, and 6.9+/-1.3 mmol/L, respectively. At rest, cerebral lactate utilization changed from a net lactate release of 0.06+/-0.01 to an uptake of 0.16+/-0.07 mmol/min during lactate infusion, with a concomitant decrease in the net glucose uptake. During exercise, the net cerebral lactate uptake was further increased to 0.28+/-0.16 mmol/min. Most (13)C-label from cerebral [1-(13)C]lactate uptake was released as (13)CO(2) with 100%+/-24%, 86%+/-15%, and 87%+/-30% at rest with and without lactate infusion and during exercise, respectively. The contribution of systemic lactate to cerebral energy expenditure was 8%+/-2%, 19%+/-4%, and 27%+/-4% for the respective conditions. In conclusion, systemic lactate is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.

A high-fat, high-calorie diet is associated with obesity and type 2 diabetes. However, the relative contribution of metabolic defects to the development of hyperglycaemia and type 2 diabetes is controversial. Accumulation of excess fat in muscle and adipose tissue in insulin resistance and type 2 diabetes may be linked with defective mitochondrial oxidative phosphorylation. The aim of the current study was to investigate acute effects of short-term fat overfeeding on glucose and insulin metabolism in young men. We studied the effects of 5 days' high-fat (60% energy) overfeeding (+50%) versus a control diet on hepatic and peripheral insulin action by a hyperinsulinaemic euglycaemic clamp, muscle mitochondrial function by 31 P magnetic resonance spectroscopy, and gene expression by qrt-PCR and microarray in 26 young men. Hepatic glucose production and fasting glucose levels increased significantly in response to overfeeding. However, peripheral insulin action, muscle mitochondrial function, and general and specific oxidative phosphorylation gene expression were unaffected by high-fat feeding. Insulin secretion increased appropriately to compensate for hepatic, and not for peripheral, insulin resistance. High-fat feeding increased fasting levels of plasma adiponectin, leptin and gastric inhibitory peptide (GIP). High-fat overfeeding increases fasting glucose levels due to increased hepatic glucose production. The increased insulin secretion may compensate for hepatic insulin resistance possibly mediated by elevated GIP secretion. Increased insulin secretion precedes the development of peripheral insulin resistance, mitochondrial dysfunction and obesity in response to overfeeding, suggesting a role for insulin per se as well GIP, in the development of peripheral insulin resistance and obesity.

The human brain releases a small amount of lactate at rest, and even an increase in arterial blood lactate during anesthesia does not provoke a net cerebral lactate uptake. However, during cerebral activation associated with exercise involving a marked increase in plasma lactate, the brain takes up lactate in proportion to the arterial concentration. Cerebral lactate uptake, together with glucose uptake, is larger than the uptake accounted for by the concomitant O(2) uptake, as reflected by the decrease in cerebral metabolic ratio (CMR) [the cerebral molar uptake ratio O(2)/(glucose+(1/2) lactate)] from a resting value of 6 to <2. The CMR also decreases when plasma lactate is not increased, as during prolonged exercise, cerebral activation associated with mental activity, or exposure to a stressful situation. The CMR decrease is prevented with combined beta(1)- and beta(2)-adrenergic receptor blockade but not with beta(1)-adrenergic blockade alone. Also, CMR decreases in response to epinephrine, suggesting that a beta(2)-adrenergic receptor mechanism enhances glucose and perhaps lactate transport across the blood-brain barrier. The pattern of CMR decrease under various forms of brain activation suggests that lactate may partially replace glucose as a substrate for oxidation. Thus, the notion of the human brain as an obligatory glucose consumer is not without exceptions.

We hypothesised that heat production of human skeletal muscle at a given high power output would gradually increase as heat liberation per mole of ATP produced rises when energy is derived from oxidation compared to phosphocreatine (PCr) breakdown and glycogenolysis. Five young volunteers performed 180 s of intense dynamic knee‐extensor exercise (≈80 W) while estimates of muscle heat production, power output, oxygen uptake, lactate release, lactate accumulation and ATP and PCr hydrolysis were made. Heat production was determined continuously by (i) measuring heat storage in the contracting muscles, (ii) measuring heat removal to the body core by the circulation, and (iii) estimating heat transfer to the skin by convection and conductance as well as to the body core by lymph drainage. The rate of heat storage in knee‐extensor muscles was highest during the first 45 s of exercise (70‐80 J s−1) and declined gradually to 14 ± 10 J s−1 at 180 s. The rate of heat removal by blood was negligible during the first 10 s of exercise, rising gradually to 112 ± 14 J s−1 at 180 s. The estimated rate of heat release to skin and heat removal via lymph flow was < 2 J s−1 during the first 5 s and increased progressively to 24 ± 1 J s−1 at 180 s. The rate of heat production increased significantly throughout exercise, being 107 % higher at 180 s compared to the initial 5 s, with half of the increase occurring during the first 38 s, while power output remained essentially constant. The contribution of muscle oxygen uptake and net lactate release to total energy turnover increased curvilinearly from 32 % and 2 %, respectively, during the first 30 s to 86 % and 8 %, respectively, during the last 30 s of exercise. The combined energy contribution from net ATP hydrolysis, net PCr hydrolysis and muscle lactate accumulation is estimated to decline from 37 % to 3 % comparing the same time intervals. The magnitude and rate of elevation in heat production by human skeletal muscle during exercise in vivo could be the result of the enhanced heat liberation during ATP production when aerobic metabolism gradually becomes dominant after PCr and glycogenolysis have initially provided most of the energy.

During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O 2 /(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio-venous differences (AV) for O 2 , glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy young subjects. In a second experiment magnetic resonance spectroscopy ( 1 H-MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AV O2 from 3.2 ± 0.1 at rest to 3.5 ± 0.2 mM (mean ± S.E.M.; P < 0.05) and the AV glc from 0.6 ± 0.0 to 0.9 ± 0.1 mM (P < 0.01). Notably, the AV lac increased from 0.0 ± 0.0 to 1.3 ± 0.2 mM at the point of exhaustion (P < 0.01). Thus, maximal exercise reduced the cerebral metabolic ratio from 6.0 ± 0.3 to 2.8 ± 0.2 (P < 0.05) and it remained low during the early recovery. Despite this, the CSF concentration of lactate postexercise (1.2 ± 0.1 mM; n = 7) was not different from baseline (1.4 ± 0.1 mM; n = 6). Also, the 1 H-MRS signal from lactate obtained after exercise was smaller than the estimated detection limit of ∼1.5 mM. The finding that an increase in lactate could not be detected in the CSF or within the brain rules out accumulation in a distribution volume and indicates that the lactate taken up by the brain is metabolized.

The metabolic activity of the brain has not been evaluated during physical exercise. In six volunteers substrate uptake by the brain was determined during graded exercise and recovery from maximal exercise by measuring the arterial‐internal jugular venous concentration differences(a–v differences). The a–v difference for lactate increased from 0.02 ± 0.08 mmol l−1 at rest to 0.39 ± 0.13 mmol l−1 during exercise and remained positive during 30 min of recovery (P < 0.05). The a–v difference for glucose (0.55 ± 0.06 mmol l−1 at rest) did not change significantly during exercise, but during the initial 5 min of recovery it increased to 0.83 ± 0.10 mmol l−1 (P < 0.05). The O2 a–v difference at rest of 3.11 ± 0.30 mmol l−1 remained stable during exercise, then increased during the initial 5 min of recovery (3.77 ± 0.52 mmol l−1) and remained high during the subsequent 30 min recovery period (3.62 ± 0.64 mmol l−1; P < 0.05). Thus the O2/glucose uptake ratio did not change during exercise (pre‐exercise 5.95 ± 0.68; post‐exercise 6.02 ± 1.39) but decreased to 4.93 ± 0.99 during the initial 5 min of recovery (P < 0.05). When lactate uptake was included, the resting O2/carbohydrate uptake ratio of 5.84 ± 0.73 was reduced to 4.42 ± 0.25 during exercise and decreased further during the recovery phase (to 3.79 ± 0.30; P < 0.05). In contrast, in the resting and immobilised rat, lactate infusion to a level similar to that obtained during maximal exercise in humans did not affect the a–v difference for lactate. The large carbohydrate uptake by the brain during recovery from maximal exercise suggests that brain glycogen metabolism is important in the transition from rest to exercise, since this would explain the significant post‐exercise decrease in the O2/carbohydrate uptake ratio.

Changes in the metabolites phosphocreatine (PCr), Pi and ATP were quantified by 31P n.m.r. spectroscopy in the human calf muscle during isometric contraction and recovery under ischaemic conditions. Time resolution of the measurements was 10 s. During a 30-60 s ischaemic isometric contraction, PCr decreased linearly at a rate of 1.17%/s (relative to the resting value) at a contraction strength equivalent to 70% of the maximal voluntary contraction (MVC) and at a rate of 2.43%/s at 90% MVC. There was a corresponding increase in Pi but the concentration of ATP did not change. pH decreased linearly during contraction by 4.22 and 8.23 milli-pH units/s at 70 and 90% MVC respectively. During a subsequent 5 min interval of ischaemic recovery, PCr, Pi, ATP, phosphomonoesters and calculated free ADP, free AMP and pH retained the value they had attained by the end of contraction with no significant recovery. Thus it is concluded that anaerobic glycolysis and glycogenolysis is halted momentarily on termination of contraction and that PCr is not resynthesized during ischaemic recovery. This paradoxical arrest of glycolytic flow in spite of the very significantly elevated concentration of potent activators such as Pi and free AMP clearly indicates that parameters other than PCr, ATP, Pi, calculated pH, free ADP and free AMP regulate glycolysis and glycogenolysis of human skeletal muscle very efficiently under ischaemic conditions.

During and after maximal exercise there is a 15–30 % decrease in the metabolic uptake ratio (O2/[glucose +1/2lactate]) and a net lactate uptake by the human brain. This study evaluated if this cerebral metabolic uptake ratio is influenced by the intent to exercise, and whether a change could be explained by substrates other than glucose and lactate. The arterial‐internal jugular venous differences (a‐v difference) for O2, glucose and lactate as well as for glutamate, glutamine, alanine, glycerol and free fatty acids were evaluated in 10 healthy human subjects in response to cycling. However, the a‐v difference for the amino acids and glycerol did not change significantly, and there was only a minimal increase in the a‐v difference for free fatty acids after maximal exercise. After maximal exercise the metabolic uptake ratio of the brain decreased from 6.1 ± 0.5 (mean ±s.e.m.) at rest to 3.7 ± 0.2 in the first minutes of the recovery (P < 0.01). Submaximal exercise did not change the uptake ratio significantly. Yet, in a second experiment, when submaximal exercise required a maximal effort due to partial neuromuscular blockade, the ratio decreased and remained low (4.9 ± 0.2) in the early recovery (n= 10; P < 0.05). The results indicate that glucose and lactate uptake by the brain are increased out of proportion to O2 when the brain is activated by exhaustive exercise, and that such metabolic changes are influenced by the will to exercise. We speculate that the uptake ratio for the brain may serve as a metabolic indicator of ‘central fatigue’.